Cellulite is a fatty substance produced by fat cells (adipocytes) and deposited mainly under the thighs and buttocks which gives the skin an “orange peel” appearance. Two competing processes involving breakdown (lypolysis) and production (lypogenesis) of fat occur in the cells. In lypolysis, triglycerides are converted into free fatty acids and glycerol by the action of triglyceride lipases. This reaction is activated by cyclic AMP which converts the lipases into active forms. Lypolysis is controlled by phosphodiesterase, an enzyme which breaks down cyclic AMP and effectively prevents lypolysis. Xanthines, such as caffeine, theobromine and theophylline can inhibit phosphodiesterase and thereby promote lypolysis. These compounds are reported to be active topically and can also temporarily dehydrate cells, making the skin look and feel firmer. Not surprisingly, xanthines are used widely in skin care products and slimming aids to prevent cellulite from accumulating.
Caffeine is a methylxanthine which is a CNS stimulant and inhibitor of phosphodiesterase. It is a white crystalline solid, soluble 1:10 in hot water, but crystallises as fine needles on cooling. It is sparingly soluble in fixed oils and ethanol. The solubility in cold water is approximately 1:50. However it is soluble 1:10 in equal parts of ethanol and water. Topical preparations containing caffeine are commonly used in anti-cellulite treatments. The preparations are either hydro-alcoholic solution/gel or cream/lotion type products. There are problems relating to irritancy or reduced efficacy with both of these types of formulations. An effective amount of caffeine cannot be kept in solution without using large amounts of ethanol. If a large amount of ethanol is used, the solution dries rapidly, leaving a white powder on the skin after application. Creams and lotions are more cosmetically acceptable, but they are perceived to be less effective because of the smaller amount of caffeine that can be solubilised. Therefore there is a need for an aesthetic and cosmetically acceptable preparation containing an effective amount of caffeine which does not crystallise out, is non-irritant and does not dry out the skin.
Salicylic acid is used in topical applications as an exfoliating agent and to remove wrinkles from under the eyes, in low concentrations (<0.2/o), often as alkali salt. It is soluble in ethanol but only sparingly soluble in water. Salicylates, and in particular, salicylic acid is a skin irritant and it is usually combined with emollients in skin care products.
In this specification, the term phospholipid refers to at least one membrane lipid or, preferably, a mixture of membrane lipids comprising phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), phosphatidyl inositol (PI), phosphatidic acid (PI) and/or phosphatidyl serine (PS). The definition includes diacyl phospholipids and their monoacyl equivalents, with either unsaturated or saturated hydrocarbon chain(s). Phospholipids are the most common examples of natural membrane lipids. They are the natural building blocks of cell membranes. Membrane lipids are essential for normal skin function. They protect the skin from irritants and alleviate the irritation. Therefore membrane lipids are commonly used in skin care preparations to confer emollient and protective functions and to control transepidermal water loss. Most commonly, they are used to form liposomes designed to carry active compounds. Liposomes are made up of one or more alternating bilayers which can sequester both oil soluble and water soluble compounds. Liposomes have poor long term storage stability, and therefore there are serious limitations in utilising liposomes to carry active compounds.
The present invention does not depend on liposome structure to entrap the active compound. It is not concerned with formation of liposomes, or with liposome entrapment. The compositions simply utilise phospholipids, particularly mixtures of diacyl and monoacyl phospholipids, to prepare easily dispersible powder compositions that form small structured lipid assemblies (SLAs) on contact with water. The SLAs may be vesicles, micelles, mixed micelles or often a heterogeneous mixture, depending on the types of phospholipid used. Typically, the SLAs have a diameter of between 0.05μ to 1μ (i.e. from 50 nm to 1000 nm). Surprisingly, it has been found that SLAs offer a valuable and effective source of natural membrane lipids that is convenient and easy to assimilate into the skin structure. The fact that the SLAs can also transport dissolved biologically active compounds is an unexpected bonus.
On p1651 of the 31st edition of Martindale The Extra Pharmacopoeia, it is disclosed that caffeine can be dissolved in concentrated solutions of alkali benzoates and salicylates. Caffeine is used orally in medicine as a CNS stimulant. It is also included in analgesics as the free base or as a water-soluble (e.g. citrate) salt. However, in skin care applications, the free base is mostly preferred due to its lipophilic properties.
There are many known caffeine preparations for anti-cellulite treatment. These contain a maximum of about 5% caffeine dissolved in ethanol or incorporated in the form of caffeine benzoate in creams and lotions.
FR-A-2627388 discloses a cream containing mucopolysaccharides, extracts of animal connective tissue and extracts of powdered cola nut (which contains caffeine), preferably together with liposomes. EP-A-260241 describes a composition comprising xanthine entrapped within liposomes. The products are intended strictly for inhalation and the presence of liposomes is required.
PCT application WO 95/34279 describes aqueous liposomal dispersions of phospholipids comprising a carboxylic acid or salicylic acid in the salt form that claim to be non-irritant and have skin beneficial properties. It would appear, from the examples disclosed, that the liposome suspensions are made from a pro-liposome composition disclosed in EP 0 158 441 B1.